www.elsevier.com/locate/apcata

Applied Catalysis A: General 286 (2005) 137–141

Zeolite-catalyzed ecofriendly synthesis of vibrindole A and

bis(indolyl)methanes

M. Karthik a, C.J. Magesh b, P.T. Perumal b, M. Palanichamy a,Banumathi Arabindoo a, V. Murugesan a,*

a Faculty of Science and Humanities, Department of Chemistry, Anna University, Chennai 600025, Indiab Organic Chemistry Division, Central Leather Research Institute, Chennai 600020, India

Received 21 October 2004; received in revised form 23 February 2005; accepted 10 March 2005

Available online 19 April 2005

Abstract

Electrophilic substitution of indoles with carbonyl compounds was carried out over HY, Hb and H-ZSM-5 zeolites as effective

heterogeneous catalysts. These zeolites afford good to excellent yield of bis(indolyl)methanes at room temperature. Vibrindole A, a novel

beneficial compound, has been successfully synthesised for the first time in the presence of zeolite in good yield. The yield of

bis(indolyl)methanes increases in the order H-ZSM-5 < Hb < HY, which is in accordance with the acid site density of the catalyst. The

catalysts can be reused five times without any loss in catalytic activity.

# 2005 Elsevier B.V. All rights reserved.

Keywords: Zeolites; Bis(indolyl)methanes; Vibrindole A; Indole; Aldehydes; Ketones

1. Introduction

Indole has been widely identified as a privileged structure

or pharmacaphore, with representation in over 3000 natural

isolates [1] and several medicinal agents of diverse

therapeutic action [2]. Diindolylmethane (DIM) (or bis(in-

dolyl)methane) is the most active cruciferous substance for

promoting beneficial estrogen metabolism in women and

men [3]. Hong et al. [4] and Kedmi et al. [5] reported

recently the potential beneficial effects of 3,30-diindolyl-

methane on the proliferation and induction of apoptosis in

human prostate and breast cancer cells. DIM has significant

physiological activity and finds useful applications as a

breast cancer preventative [6].

Over the past decade, a number of bisindole metabolites

have been isolated from various genera of sponges from

natural sources [7]. The electrophilic substitution reaction of

indole with aldehydes/ketones affords bis(indolyl)methanes

using protic acids [8] and Lewis acids [9,10] as catalysts.

* Corresponding author. Tel.: +91 44 22301168; fax: +91 44 22200660.

E-mail address: v_murugu@hotmail.com (V. Murugesan).

0926-860X/$ – see front matter # 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.apcata.2005.03.017

Many Lewis acids like trifluoroboron etherate and alumi-

nium chloride promote the electrophilic substitution

reaction of indole, but they generate harmful wastes that

pose environmental problems. In addition, the reaction

proceeds with more than stoichiometric amounts of Lewis

acids as they are trapped by nitrogen [11]. Many Lewis acids

are deactivated or decomposed by nitrogen-containing

reactants. D’Auria [12] reported the photochemical reaction

of an aromatic aldehyde with indole, giving 3,30-diindo-

lylmethanes in ca. 50% yield. Recently, lithium perchlorate

[13] and lanthanide triflates [14] have been used as Lewis

acid catalysts in the synthesis of bis(indolyl)methanes. But

the reaction requires long a reaction time; besides, the

catalyst is very expensive. Several catalysts have been

reported recently, such as InCl3 [15], I2 [16], N-Bromo-

Succinimide (NBS) [17], montmorillonite clay [18], ionic

liquid [19,20], NaHSO4�SiO2/Amberlyst-15 [21] and

KHSO4 [22], for the synthesis of bis(indolyl)methanes.

Most of these catalysts so far reported suffer from one or

more disadvantages. Hence, there is a need for an efficient,

ecofriendly and recyclable catalyst for the synthesis of

bis(indolyl)methanes and their analogues. Our group

M. Karthik et al. / Applied Catalysis A: General 286 (2005) 137–141138

recently reported the synthesis and characterisation of

bis(indolyl)methanes and tris(indolyl)methanes over zeo-

karb-225 (sulfonated polystyrene beads) as a recyclable

heterogeneous catalyst [23]. This group also reported for the

first time a zeolite-catalyzed reaction of indole with selected

aldehydes to yield bis(indolyl)methanes at room tempera-

ture [24].

In continuation of our ongoing interest, we herein report

the use of zeolites as catalysts in the electrophilic

substitutions of indole and substituted indole with a variety

of aldehydes and ketones, affording excellent yields of

bis(indolyl)methanes at room temperature. This method has

provided an easy access to the naturally occurring and

bioactive bis(indolyl)methanes. The first successful synth-

esis of a novel beneficial compound, vibrindole A,

employing an ecofriendly zeolite catalyst is a better method

than the methods reported already in the literature [25–29].

Vibrindole A is a bacterial metabolite having antibacterial

activity against Staphylococcus aureus, S. albus and B.

subtilis, where gentamycin is used as the standard drug

[22,30]. The significant findings as well as the advantages of

this method over the existing synthetic routes are discussed

in this article.

2. Experimental

2.1. Preparation of the catalysts

The Na-forms of b (Si/Al = 15), Y (Si/Al = 3) and ZSM-

5 (Si/Al = 53) zeolites were obtained from Sud-Chemie

India Ltd. They were converted into H-form by repeated ion

exchange with 1 M ammonium nitrate solution at 80 8C and

subsequent calcination of the filtered material in air at

550 8C. The surface-passivated zeolite HY (SPHY) was

obtained by the method described by Andy et al. [31]. HY

(0.25 g) and hexane (3 ml) were stirred under argon

atmosphere, to which 0.1 ml of tetraethylorthosilicate

(TEOS) was added and the stirring was continued for 3 h.

Then, the zeolite was filtered and washed with hexane. The

surface of the zeolite was coated with silica [32,33].

2.2. Characterisation

Nitrogen adsorption/desorption experiments were carried

out using a Quantachrome Autosorb 1 sorption analyser.

Prior to the adsorption of nitrogen at 77 K, the samples were

outgassed for 3 h at 250 8C under 10�5 mbar. In situ DRIFT

Table 1

Physicochemical characterisation of zeolite catalysts

S. no. Catalyst Si/Al ratio Crystal size (mm) BET s

1 HY 3 0.5 648

2 Hb 15 1.0 575

3 H-ZSM-5 53 3.1 386

4 SPHY – – 504

(pyridine adsorption) spectra were recorded in a Nicolet

Avatar 360 FT-IR spectrophotometer equipped with a high

temperature vacuum chamber. Approximately 10 mg of the

sample was taken in the sample holder and dehydrated at

400 8C for 6 h under vacuum. The spectrum was recorded

after cooling the sample to room temperature. Then,

pyridine was adsorbed at room temperature. The physically

adsorbed pyridine was removed by heating the sample at

120 8C under vacuum (10�5 mbar) for 30 min. The material

was cooled to room temperature and the infrared spectrum

was recorded in the range 1700–1400 cm�1 (pyridine

adsorption region). The number of Bronsted and Lewis

acid sites was calculated by measuring the integrated

absorbance of bands representing pyridinium ion formation

and coordinatively bonded pyridine using the extinction

coefficients (e) [34–36].

2.3. Catalytic studies

The reaction of indole (5 mmol) and aldehyde or ketone

(2.5 mmol) in the presence of zeolite (0.5 g, activated at

300 8C for 3 h) using dichloromethane (10 ml) as the solvent

was carried out in a 50 ml round-bottomed flask; the reaction

mixture was stirred continuously. The reaction proceeded

smoothly at room temperature. After complete conversion as

indicated by TLC, the reaction mixture was filtered and the

catalyst was washed thoroughly with dichloromethane,

filtered and dried. The combined washings and the filtrate

were evaporated and concentrated in vacuum. The crude

product was purified by column chromatography on a silica

gel (Merck, 60–120 mesh, ethyl acetate/petroleum ether-1:4).

The recovered catalyst was reactivated at 500 8C in the

presence of moisture-free air and was reused. The same

reaction was carried out under identical conditions but without

the catalyst. There was no reaction observed in the absence of

catalyst. The products were identified by GC–MS (Hewlett

Packard, HP-5890 gas chromatograph with flame ionization

detector, SB 30 packed column), FT-IR (Nicolet Avatar 360

FT-IR), 1H NMR (Bruker, 300 MHz in DMSO, internal

standard TMS) and 13C NMR (Bruker, 75 MHz in CDCl3).

3. Results and discussion

3.1. Characterisation

The physico-chemical properties of the zeolites are given

in Table 1. It can be seen from Table 1 that BET surface area

urface area (m2/g) Pore diameter (nm) Pore volume (cm3/g)

0.74 0.285

0.57 � 0.75 0.225

0.54 � 0.56 0.148

0.74 0.278

M. Karthik et al. / Applied Catalysis A: General 286 (2005) 137–141 139

Table 2

Bronsted and Lewis acidity values of the zeolites

S. no. Catalyst Bronsted (B) acid site (mmol/g) Lewis (L) acid site (mmol/g) B/L acid site ratio (mmol/g)

1 HY 0.28 0.31 0.90

2 Hb 0.25 0.22 1.13

3 H-ZSM-5 0.17 0.16 1.06

and pore volume of the zeolites decreases in the order

HY > Hb > H-ZSM-5. The peaks at 1445, 1595 and

1632 cm�1 correspond to pyridine coordinated to Lewis

acid sites [37] and the peak at 1543 cm�1 corresponds to

pyridine bound to Bronsted acid sites [38]. The peak at

1491 cm�1 is assigned to both Bronsted and Lewis acid sites

[39]. These acid sites are responsible for the catalytic

activity of the zeolites. The acidity of the zeolite catalyst was

calculated; the values are given in Table 2. This study reveals

that the acidity of the catalysts decreases in the order

HY > Hb > H-ZSM-5.

3.2. Synthesis of vibrindole A and bis(indolyl)methanes

The reaction of indole with benzaldehyde was carried out

over HY, Hb and H-ZSM-5 zeolites. The yields of

bis(indolyl)methanes are given in Table 3. The yield of

bis(indolyl)methanes increases in the order H-ZSM-

5 < Hb < HY, which is the same as the order of the

increasing acid site density values of the catalysts. These

results are in good agreement with DRIFT measurements.

The reaction is assumed to take place only on the external

surface of the zeolite, due to the inability of the product to

diffuse into the zeolite channel structure. In order to support

this assumption, we carried out the reaction on surface-

passivated HY (SPHY) zeolite. The yield of bis(indolyl)-

methanes was drastically suppressed on the surface

passivated zeolite (10%); presumably almost all the acid

sites on the external surface are passivated by the amorphous

silica layer. These results suggest that the reaction probably

takes place mainly on the external acid sites of the zeolite

[24].

The molecular dimensions (1.0622 nm � 1.0875 nm �1.1167 nm) of the bis(indolyl)phenylmethanewere calculated

from Cambridge Structural Database using the three-

dimensional coordinates of the product [40]. The dimensions

of the products are greater than the pore dimensions of the

Table 3

The yield of bis(indolyl)methanes over zeolite catalysts

S. no. Catalyst Time (h) Yield (%)a,b

1 HY 2.0 80

2 Hb 2.5 75

3 H-ZSM-5 4.5 40

4 SPHY 4.0 10

Catalyst weight, 0.5 g; solvent, dichloromethane; room temperature.a All the products were characterised by FT-IR, 1H NMR, 13C NMR and

GC–MS.b Isolated yields after purification.

tested zeolites (Table 1). Thus the computational modeling

analysis also reveals that the bis(indolyl)phenylmethane is

most probably formed on the external surface of the catalyst

rather than inside the pores of the zeolites. The minimum

energy conformations (3D-model) of bis(indolyl)phenyl-

methane and vibrindole A are depicted in Fig. 1.

The crystal size of the zeolites plays a crucial role in the

product formation. The yield of the product increases with

decrease in crystal size of the zeolites: H-ZSM-

5 > Hb > HY. The number of external surface acid sites

is reduced with increase in crystal size of the zeolites, as

reported already in the literature [31,32]. Hence, the yield of

bis(indolyl)methanes is found to be high for those zeolites

with low Si/Al ratio and small crystal size since such zeolites

possess more density of external surface acid sites.

The electrophilic substitution of indole (5 mmol) with

acetaldehyde (2.5 mmol) in the presence of HY (0.5 g,

activated at 300 8C for 3 h) in dichloromethane (10 ml)

solvent produced vibrindole A in excellent yield at room

temperature (Scheme 1). Comparison of the yield and other

reaction conditions of the synthesis of vibrindole A already

reported in the literature and those in the present method is

Fig. 1. The minimum energy conformation structures of: (a) vibrindole A

and (b) bis(indolyl)phenylmethane.

M. Karthik et al. / Applied Catalysis A: General 286 (2005) 137–141140

Scheme 1.

Table 4

Comparison of synthesis procedures for vibrindole A

S. no. Reagent Temperature (8C) Time Yielda (%) Literature reference

1 CH3CHO, CH3COOH Room temperature 10 days 58 [25]

2 Propiolic acid, MeOH Reflux 5 h 45 [26]

CO2

3 An oxazolidineb, MeCN, CF3COOH Room temperature 15 min 25 [27]

4 EtOH, DMCDc, aq. NaClO4, Pt-electrode Room temperature Not stated 86 [28]

5 MeCH = N+(Bn)O�, Me3SiCl, CH2Cl2 Room temperature 17 h 83 [29]

6 Present method CH3CHO, CH2Cl2, HY zeolite (0.5 g) Room temperature 2 h 85 –

a Isolated yields after purification.b 2-Methyl-3-phenyloxazolidine.c 2,6-Di-O-methyl-b-cyclodextrin.

Scheme 2.

shown in Table 4. It is clearly evident that the present method

yields 85 % in about 2 h of reaction with an ecofriendly

catalyst.

Similarly, the analogous reaction of indole with aromatic

or aliphatic aldehyde/ketone produced azafulvenium salt

[41], which then reacted further with a second indole

molecule to form bis(indolyl)methane in good yield

(Scheme 2). Aromatic aldehydes with electron-donating

substituents gave excellent yields, whereas aromatic

aldehydes with electron-withdrawing substituents gave poor

yields (Table 5). Chloro- and nitro-substituted aldehydes

also required longer reaction time to produce comparable

yield than their electron-donating counterparts. Aldehydes

Table 5

Synthesis of vibrindole A and bis(indolyl)methanes in the presence of HY zeoli

S. no. Indole Aldehyde/ketone

1 1a CH3CHO (2a)

2 1a CH3(CH2)4CHO (2b)

3 1a C6H5CHO (2c)

4 1a o-O2NC6H4CHO (2d)

5 1a m-O2N C6H4CHO (2e)

6 1a p-CH3OC6H4CHO (2f)

7 1a p-ClC6H4CHO (2g)

8 1a p-CH3C6H4CHO (2h)

9 1a m-CH3C6H4CHO (2i)

10 1a 4-OH-3-CH3O-C6H3CHO (2j)

11 1a CH3COCH3 (2k)

12 1a CH3COC6H5 (2l)

13 1a C6H5COC6H5 (2m)

14 1a Cyclohexanone (2n)

15 1b p-CH3OC6H4CHO (2f)

16 1b m-O2NC6H4CHO (2e)

Catalyst weight 0.5 g; Solvent, Dichloromethane, Room temperature.a Isolated yields after purification.b All the products were characterised by FT-IR, 1H NMR, 13C NMR and GC–c HY catalyst weight 1 g instead of 0.5 g.

like 4-methoxybenzaldehyde and 4-hydroxy-3-methoxy-

benzaldehyde (vanillin) reacted rapidly with indole, giving

the corresponding product in excellent yield within 1.5 h.

The reaction of hexanal with indole gave the product with

74% yield. Ketones reacted slowly with indole, giving

moderate yields and the reactions of the three ketones with

indole took longer times. The time required to complete the

reaction was reduced by using twice the amount of the

catalyst (1 g of HY) to obtain comparable yields. Never-

theless, cyclohexanone afforded 80% yield of the desired

product, while acetone and acetophenone gave approxi-

te

Reaction time (h) Product Yield (%)a,b

2.0 3a 85

2.0 3b 74

2.0 3c 82

4.0 3d 65

4.0 3e 62

1.5 3f 86

5.0 3g 64

1.5 3h 85

2.0 3i 75

1.5 3j 88

4.5c 3k 75

6c 3l 70

12c 3m –

2.5c 3n 80

1.5 3o 83

4.0 3p 70

MS.

M. Karthik et al. / Applied Catalysis A: General 286 (2005) 137–141 141

mately 75 and 70% yield, respectively. Benzophenone did

not react with indole because of steric hindrance, as reported

by Chakrabarty et al. [18]. The reaction of 2-methylindole

with p-methoxybenzaldehyde and m-nitrobenzaldehyde also

gave the corresponding products in about 83 and 70% yields,

respectively.

The reaction was also performed by varying the amount of

the catalyst. The increase in the yield of bis(indolyl)methanes

was linear with increase in the amount of catalyst (100–

500 mg). The catalyst is readily recyclable and can be reused

five times without any loss of catalytic activity. Further studies

are in progress for the synthesis of a variety of heterocyclic

compounds employing zeolites and modified zeolites.

4. Conclusion

Zeolites have been proved to be an effective catalyst for

the reaction of indole and substituted indoles with carbonyl

compounds, affording good yields of bis(indolyl)methanes.

The synthesis of vibrindole A in the presence of zeolite

catalyst is better than previous syntheses. The catalyst is

found to be mild, cheap and commercially available. This

new strategy offers several advantages, including simple

experiment conditions, high yield and readily recyclable

catalyst. Thus, zeolites could be a viable, ecofriendly and

recyclable solid acid catalyst for the synthesis of vibrindole

A and bis(indolyl)methanes.

Acknowledgements

We gratefully acknowledge the financial support and

research fellowship for the project funded by the Department

of Science and Technology (DST), New Delhi, India

(Project Sanction no. SR/S1/PC-24/2003). We thank Mr.

Saraboji and Mr. Sampath, Department of Crystallography

and Biophysics, University of Madras, Chennai, for carrying

out the molecular modeling analysis.

References

[1] Based on a survey of the Beilstein database.

[2] A. Kleenman, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical

Substances, fourth ed., Thieme, New York, 2001.

[3] M.A. Zeligs, J. Med. Food 1 (1998) 67.

[4] C. Hong, G.L. Firestone, L.F. Bjeldanes, Biochem. Pharmacol. 63

(2002) 1085.

[5] M.N. Kedmi, S. Yannai, A. Haj, F.A. Fares, Food Chem. Toxicol. 41

(2003) 745.

[6] J.J. Michnovicz, H.L. Bradlow, Proc. R. Soc. Edinburgh 12 (1989)

1571.

[7] D.J. Faulkner, Nat. Prod. Rep. 18 (2001) 1.

[8] M. Roomi, S. MacDonald, Can. J. Chem. 48 (1970) 139.

[9] W.E. Noland, M.R. Venkiteswaren, C.G. Richards, J. Org. Chem. 26

(1961) 4241.

[10] G. Babu, N. Sridher, P.T. Perumal, Synth. Commun. 30 (2000) 1609.

[11] S. Kobayashi, M. Araki, M. Yasuda, Tetrahedron Lett. 36 (1995) 5773.

[12] M. D’Auria, Tetrahedron 47 (1991) 9225.

[13] J.S. Yadav, B.V.S. Reddy, Ch.V.S.R. Murthy, G.M. Kumar, Ch. Madan,

Synthesis (2001) 783.

[14] D. Chen, L. Yu, P.G. Wang, Tetrahedron Lett. 37 (1996) 4467.

[15] J.S. Yadav, B.V.S. Reddy, G. Satheesh, A. Prabhakar, A.C. Kunwar,

Tetrahedron Lett. 44 (2003) 2221.

[16] B.P. Bandgar, K.A. Shaikh, Tetrahedron Lett. 44 (2003) 1959.

[17] H. Koshima, W. Matsuaka, J. Heterocycl. Chem. 39 (2002) 1089.

[18] M. Chakrabarty, N. Ghosh, R. Basak, Y. Harigaya, Tetrahedron Lett.

43 (2002) 4075.

[19] J.S. Yadav, B.V.S. Reddy, S. Sunitha, Adv. Synth. Catal. 345 (2003)

349.

[20] S.J. Ji, M.F. Zhou, D.G. Gu, Z.Q. Jiang, T.P. Loh, Eur. J. Org. Chem.

(2004) 1584.

[21] C. Ramesh, J. Banerjee, R. Pal, B. Das, Adv. Synth. Catal. 345 (2003)

557.

[22] R. Nagarajan, P.T. Perumal, Chem. Lett. 33 (2004) 288.

[23] C.J. Magesh, R. Nagarajan, M. Karthik, P.T. Perumal, Appl. Catal. A:

Gen. 266 (2004) 1.

[24] M. Karthik, A.K. Tripathi, N.M. Gupta, M. Palanichamy, V. Muru-

gesan, Catal. Commun. 5/7 (2004) 371.

[25] A. Kamal, A.A. Qureshi, Tetrahedron 19 (1963) 512.

[26] S.H. Zee, C.S. Chen, J. Chin. Chem. Soc. 21 (1974) 229.

[27] H. Singh, R. Sarin, K. Singh, Heterocycles 24 (1986) 3039.

[28] K. Suda, T. Takanami, Chem. Lett. (1994) 1915.

[29] J.N. Denis, H. Mauger, Y. Vallee, Tetrahedron Lett. 38 (1997)

8515.

[30] R. Bell, S. Carmeli, N. Sar, J. Nat. Prod. 57 (1994) 1587.

[31] P. Andy, J. Garcia-Martinez, G. Lee, H. Gonzalez, C.W. Janes, M.E.

Davis, J. Catal. 192 (2000) 215.

[32] P.J. Kunkeler, D. Moeskops, H. Van Bekkum, Microporous Mater. 11

(1997) 313.

[33] K.K. Cheralathan, I.S. Kumar, M. Palanichamy, V. Murugesan, Appl.

Catal. A: Gen. 241 (2003) 247.

[34] E.P. Parry, J. Catal. 2 (1963) 371.

[35] C.A. Emeis, J. Catal. 141 (1993) 347.

[36] M. Karthik, A.K. Tripathi, N.M. Gupta, A. Vinu, M. Hartmann, M.

Palanichamy, V. Murugesan, Appl. Catal. A: Gen. 268 (2004) 139.

[37] M.L. Occelli, S. Biz, A. Auroux, G.J. Ray, Microporous Mesoporous

Mater. 26 (1998) 193;

A. Corma, Chem. Rev. 95 (1995) 559.

[38] B. Chakraborty, B. Viswanathan, Catal. Today 49 (1999) 253.

[39] F.M. Bautista, J.M. Campelo, A. Garcia, D. Luna, J.M. Marinas, A.A.

Romero, J.A. Navio, M. Macias, J. Catal. 145 (1994) 107.

[40] M.R. Mason, T.S. Barnard, M.F. Segla, B. Xie, K. Kirschbaum, J.

Chem. Crystallogr. 33 (2003) 531.

[41] W. Remers, Chem. Heterocycl. Compd. 25 (1972) 1.